Variant 2-63933817-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016516.3(VPS54):c.1595T>C(p.Val532Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VPS54
NM_016516.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.949

Variant links:

Genes affected

VPS54 (HGNC:18652): (VPS54 subunit of GARP complex) This gene encodes for a protein that in yeast forms part of a trimeric vacuolar-protein-sorting complex that is required for retrograde transport of proteins from prevacuoles to the late Golgi compartment. As in yeast, mammalian Vps54 proteins contain a coiled-coil region and dileucine motifs. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Jul 2008]

VPS54 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035045713).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS54	NM_016516.3 linkuse as main transcript	c.1595T>C	p.Val532Ala	missense_variant	12/23	ENST00000272322.9	NP_057600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9 linkuse as main transcript	c.1595T>C	p.Val532Ala	missense_variant	12/23	5	NM_016516.3	ENSP00000272322	P1	Q9P1Q0-1
VPS54	ENST00000409558.8 linkuse as main transcript	c.1559T>C	p.Val520Ala	missense_variant	12/23	1		ENSP00000386980		Q9P1Q0-4
VPS54	ENST00000354504.7 linkuse as main transcript	c.1136T>C	p.Val379Ala	missense_variant	9/20	1		ENSP00000346499		Q9P1Q0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250988

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.1595T>C (p.V532A) alteration is located in exon 12 (coding exon 11) of the VPS54 gene. This alteration results from a T to C substitution at nucleotide position 1595, causing the valine (V) at amino acid position 532 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.48

DANN

Benign

0.96

DEOGEN2

Benign

0.044

.;.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.41

.;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.23

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.80

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.099

MutPred

0.34

.;.;Loss of helix (P = 0.0041);

MVP

0.082

MPC

0.042

ClinPred

0.026

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over